Preterm infants, particularly those of low birth weight and gestational age, often present neurodevelopmental deficits which include global cognitive delay, cerebral palsy, blindness, and deafness. Deficits such as cognitive delay and cerebral palsy may be attributed, at least in part, to hypoxic/ischemic damage in white and/or grey matter of the brain.
A common example of white matter injury observed in infants as a complication of premature birth is referred to as periventricular leukomalacia (PVL). PVL is the principal neuropathological correlate of cerebral palsy. The lesion is defined by focal necrosis of the deep periventricular white matter involving all cellular components, combined with a more diffuse white matter injury that appears selective for developing oligodendrocytes (OLs) (Gilles and Averill (1977) Ann. Neurol. 2:49-56; Dambska et al. (1989) J. Child Neurol. 4:291-298; and Rorke (1998) In Pathology of Perinatal Brain Injury New York: Raven). Reduced cerebral myelin is the most prominent subsequent cerebral abnormality observed in premature infants with evidence of PVL in the neonatal period (Paneth et al. (1990) J. Pediatr. 116:975-984; Rorke (1992) Brain Pathol. 2:211-221; Iida et al. (1995) Pediatr. Neurol. 13:296-304; Olsen et al. (1997) Ann. Neurol. 41:754-761; Skranes et al. (1997) Neuropediatrics 28:149-154; and Inder et al. (1999) Ann Neurol. 46:755-760).
A propensity to cerebral ischemia caused by impaired cerebrovascular autoregulation, combined with a selective vulnerability of immature OLs to ischemic injury (Volpe (1997) Brain Dev. 19:519-534), may contribute to the prevalence of this lesion in the preterm infant. Developing OLs in vitro have been demonstrated to be more vulnerable than are mature, myelin basic protein (MBP)-expressing OLs to oxidative stress (Back et al. (1998) J. Neurosci. 18:6241-6253) and to glutamate receptor (GluR)-mediated ischemic death (Fern and Moller (2000) J. Neurosci. 20:34-42). OLs appear to be more vulnerable than are other glia when exposed to hypoxia/hypoglycemia in vitro (Lyons and Kettenmann (1998) J. Creb. Blood Flow Metab. 18:521-530). Furthermore, a number of in vivo studies have demonstrated selective white matter injury after experimental hypoxia/ischemia in the rat brain during early postnatal development (Rice et al. (1981) Ann. Neurol. 9:131-134; Towfighi et al. (1991) Acta Neuropathol. 81:578-587; Sheldon et al. (1996) Biol. Neonate 69:327-341; Yue et al. (1997) Neuropathol. Appl. Neurobiol. 23:16-25; Ikeda et al. (1998) Am. J. Obstet. Gynecol. 178:24-32; Reddy et al. (1998) Pediadr. Res. 43:674-682; and Matsuda et al. (1999) Am. J. Obstet. Gynecol. 181:725-730).
Both clinical and experimental studies indicate that hypoxia/ischemia is a major underlying cause of PVL. Experimental models of ischemia in immature animals implicate glutamate as a critical factor in the pathogenesis of brain injury. Hypoxic/ischemic conditions result in elevated cerebral glutamate levels in the immature rat brain, measured by in vivo microdialysis (Benveniste et al. (1984) J. Neurochem. 4:1369-1374; Silverstein et al. (1991) Pediatr. Res. 30:587-590). Clinical relevance of the experimental studies is suggested by the demonstration of elevated glutamate in the CSF of term infants after perinatal hypoxia/ischemia (Hagberg (1992) Biol. Neonate 66:205-213). Glutamate has been shown to be toxic to oligodendroglia in vivo and in vitro by receptor-independent (Oka et al. (1993) J. Neurosci. 13:1441-1453; Yoshioka et al. (1996) J. Neurochem. 64:2442-2448; and Back et al. (1998) J. Neurosci. 18:6241-6253) and receptor-mediated mechanisms (Yoshioka et al. (1995) J. Neurochem. 64:2442-2448; Yoshioka et al. (1996) J. Neurosci. Res. 46:427-438; Matute et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94:8830-8835; McDonald et al. (1998) Nat. Med. 4:291-297; and Pitt et al. (2000) Nat. Med. 6:67-70). OLs express functional GluRs in vitro, and these are exclusively of the non-NMDA subtype (Gallo et al. (1994) Glia 11:94-101; Patneau et al. (1994) Neuron 12:357-371).